Phenoxypropanolamines, method for producing them and pharmaceutical compositions containing them

ABSTRACT

The invention relates to compounds of formula (I) 
                 
 
where
     R 1  represents a hydrogen or halogen atom or an —S(O) z —(C 1 -C 4 )alkyl, —S(O) z —(C 1 -C 4 )R 3 , —SO 2 —NH—(C 1 -C 4 )alkyl, —NHCO(C 1 -C 4 ) alkyl, —CO(C 1 -C 4 )alkyl or —NHSO 2 —(C 1 -C 4 )alkyl group;   m and n independently represent 0, 1 or 2;   A represents a group of formula (a) or (b): 
                 
 
where
   X is N or CH;   R 2  represents an —SO 2 —R 3 , —CO—R 3  or —CO—(C 1 -C 4 )—alkyl group;   R 3  represents a phenyl group, optionally substituted by a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, one or two halogen atoms or a heterocycle;   R 4  represents a hydrogen or halogen atom or a (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, —COOH, —COO(C 1 -C 4 )alkyl, —CN, —CONR 5 R 6 , —NO 2 , —NHSO 2 (C 1 -C 4 )alkyl or —SO 2 NR 5 R 6  group;   z is 1 or 2;   R 5  and R 6  independently represent a hydrogen atom or a (C 1 -C 4 )alkyl, phenyl or phenyl (C 1 -C 4 )alkyl group;
 
and their salts or solvates, to a process for their preparation, to synthetic intermediates and to the pharmaceutical compositions comprising them.

The present invention relates to novel phenoxypropanolamines, to thepharmaceutical compositions comprising them, to a process for theirpreparation and to intermediates in this process.

BE 902897 discloses aryloxypropanolamines carrying a(4-piperidinin-1-yl)-substituted group on the amine, these compoundshaving a beta-1-blocking and alpha-blocking activity.

J. Org. Chem., 1988, 63, 889-894, describes other aryloxypropanolaminescarrying a (4-piperidin-1-yl)-substituted group on the amine.

It has now been found that novel phenoxy-propanolamines carrying a(4-piperidin-1-yl)-substituted group on the amine have an agonistactivity with respect to beta-3-adrenergic receptors.

The beta-3-adrenergic receptor has formed the subject of numerousstudies targeted at synthesizing compounds which are agonists withrespect to this receptor, these compounds exerting a significantantiobesity and antidiabetic effect in man, as described, for example,by Weyer, C et al., Diabetes Metab., 1999, 25(1), 11-21.

Thus, the present invention relates, according to one of its aspects, tophenoxy-propanolamines of formula (I)

where

-   R₁ represents a hydrogen or halogen atom or an    —S(O)_(z)—(C₁-C₄)alkyl, —S(O)_(z)—(C₁-C₄)R₃, —SO₂—NH—(C₁-C₄)alkyl,    —NHCO(C₁-C₄)alkyl, —CO(C₁-C₄)alkyl or —NHSO₂—(C₁-C₄)alkyl group;-   m and n independently represent 0, 1 or 2;-   A represents a group of formula (a) or (b):    where-   x is N or CH;-   R₂ represents an —SO₂—R₃, —CO—R₃ or —CO—(C₁-C₄)-alkyl group;-   R₃ represents a phenyl group, optionally substituted by a    (C₁-C₄)alkyl or (C₁-C₄)alkoxy group, one or two halogen atoms or a    heterocycle;-   R₄ represents a hydrogen or halogen atom or a (C₁-C₆)alkyl,    (C₁-C₄)alkoxy, —COOH, —COO(C₁-C₄)alkyl, —CN, —CONR₅R₆, —NO₂,    —NHSO₂(C₁-C₄)alkyl or —SO₂NR₅R₆ group;-   z is 1 or 2;-   R₅ and R₆ independently represent a hydrogen atom or a (C₁-C₄)alkyl,    phenyl or phenyl(C₁-C₄)alkyl group;    and their salts or solvates.

In the present description, the terms “(C₁-C₄)alkyl” and “(C₁-C₆)alkyl”denote monovalent radicals of a respectively C₁-C₄ and C₁-C₆ hydrocarboncomprising a straight or branched saturated chain.

In the present description, the term “halogen” denotes an atom chosenfrom chlorine, bromine, iodine and fluorine.

The salts of the compounds of formula (I) according to the presentinvention comprise both addition salts with pharmaceutically acceptableinorganic or organic acids, such as the hydrochloride, hydrobromide,sulfate, hydrogensulfate, dihydrogenphosphate, citrate, maleate,tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate,and the like, and addition salts which make possible suitable separationor crystallization of the compounds of formula (I), such as the picrate,the oxalate or the addition salts with optically active acids, forexample camphorsulfonic acids and mandelic or substituted mandelicacids.

When the compounds of formula (I) possess a free carboxyl group, thesalts also comprise the salts with inorganic bases, preferably thosewith alkali metals, such as sodium or potassium, or with organic bases.

The optically pure stereoisomers and the mixtures of isomers of thecompounds of formula (I), due to the asymmetric carbons or to thesulfinyl group, when z is 1 in the meaning of R₁, in any proportion,form part of the present invention.

Preferred compounds are those where the (C₁-C₄)alkyl group is a methylor ethyl group.

Other further preferred compounds are those where n and m are zero.

Preferred compounds of the present invention comprise the compounds offormula (I) where A is a group (a), X is N and the NHR₂ group is in the5 position of the pyridine.

Other preferred compounds of the present invention comprise thecompounds of formula (I) where A is a group (b) and the R₄ group is inthe 4 position of the benzene.

Other preferred compounds are those where A is a group (b) and R₄ ischosen from —COOH, —COO(C₁-C₄)-alkyl, —CN, —NO₂, —CONR₂R₃,—NHSO₂—(C₁-C₄)alkyl or —SO₂NR₅R₆.

The compounds of formula (I) can be prepared by treating a compound offormula (II)

in which R₁ is as indicated above, P′ is a protective group and L is agroup of formula (c) or (d)

where Gp is a leaving group, such as tosylate, mesylate or a halogenatom, with an amine of formula (III)

in which n and m are as defined above, the group P′ being cleavedaccording to conventional methods and the compound of formula (I) thusobtained optionally being converted into one of its salts.

More particularly, the reaction between the compounds of formula (II)and (III) is carried out in an organic solvent, such as a lower alcohol,for example methanol, ethanol and isopropanol; dimethyl sulfoxide; alinear or cyclic ether; or an amide, such as dimethylformamide ordimethylacetamide; using at least equimolecular amounts of thereactants, optionally in a slight excess of amine.

The temperature of the reaction is between ambient temperature and thereflux temperature of the solvent chosen.

Use may be made, as protective groups P′, of the conventional protectivegroups for hydroxyl groups, such as, for example, methoxyethoxymethyl(MEM), benzyl, benzoyl or silyl ethers, such as, for example, thetert-butyldimethylsilyl ether (TBDMS).

The cleaving of these protective groups is carried out according to thestandard methods according to the protective group chosen and accordingto the reactivity of the other groups present, in the case of the benzylgroup, for example, by hydrogenation in the presence of a catalyst, suchas Pd/C, in a suitable solvent; in the case of MEM or of TBDMS, it isalso possible to use an acid, such as trifluoroacetic acid; in the caseof benzoyl, a transesterification reaction with an alkanol in a basicmedium can be carried out.

The epoxides of formula (II) are compounds which are known in theliterature or alternatively they can be prepared by processes analogousto those described in the literature. Some epoxides of formula (II) are,for example, disclosed in WO 96/04233 and in U.S. Pat. No. 4,396,629.

Some of the amines of formula (III) are novel compounds and constituteanother aspect of the present invention.

Thus, according to another of its aspects, the present invention relatesto amines of formula (III′)

where n, m, X and R₂ are as defined above, and their salts or solvates.

These amines can be prepared by reaction of the compounds of formula(IV)

in which P″ is a protective group, such as tert-butoxy-carbonyl orbenzyloxycarbonyl, with a radical Cl—R₂, where R₂ is as described aboveand Hal is a halogen atom, in a suitable solvent, such as, for example,pyridine, dimethylformamide or dimethyl sulfoxide, and by removal of thegroup P″ by hydrogenation or by treatment in an acidic medium, such ashydrochloric acid in ethyl acetate or in ethanol.

The starting amines of formula (IV) can be prepared by reaction ofsuitable pyridines of formula (V)

where Hal represents a halogen atom and R₂ and m are as defined above,with a piperidine of formula (VI) below

where n is as defined above and P″ represents a protective group, in anorganic solvent in the presence of a base.

Use may indeed be made, as reaction solvent, of, for example,dimethylformamide, pyridine, dimethyl sulfoxide, a linear or cyclicether, or a chloridated solvent, such as dichloromethane.

Use may be made, as base, of, for example, an alkaline hydroxide, analkaline carbonate, such as potassium carbonate, or a tertiary amine,such as triethylamine.

The above condensation reaction is completed in a few hours, normally in2-12 hours.

The reaction temperature is between ambient temperature and the refluxtemperature of the solvent chosen.

Use may be made, as protective groups P″, of, for example, theprotective groups indicated for the products of formula (IV).

The cleaving of these protective groups is carried out according to thestandard methods described for the protective group chosen; in the caseof tert-butoxycarbonyl, for example, the cleaving is normally carriedout by acid hydrolysis.

Other novel intermediates which form part of the present invention arethe amines of formula (III″)

where

-   P^(o) is a tert-butoxycarbonyl group;-   n and m are 0, 1 or 2;-   R^(o) ₄ is a group chosen from —COOH, —COO(C₁-C₄)-alkyl, —CONR^(o)    ₅R^(o) ₆ and —NHSO₂(C₁-C₄)alkyl;-   R^(o) ₅ and R^(o) ₆ independently represent a hydrogen atom or a    (C₁-C₄)alkyl group;    and their salts or solvates.

Compounds of formula (III″) which are particularly preferred are thosewhere n is 0, m is 0 or 1 and R^(o) ₄ is —COO(C₁-C₄)alkyl.

The compounds of formula (III″) can be prepared analogously to the abovecompounds (IV).

The compounds of formula (I) have shown a very powerful affinity withrespect to beta-3 receptors.

The activity of the compounds of the present invention with respect tobeta-3 agonist activity was demonstrated using in vitro tests on thehuman colon according to the method disclosed in EP-B-436 435 and in T.Croci et al., Br. J. Pharmacol., 1997, 122, 139P.

More particularly, it has been found that the compounds of formula (I)are much more active on the isolated colon than on the atrium and on thetrachea.

These surprising properties of the compounds of formula (I) make itpossible to envisage their use as medicaments with a beta-3 action.

Furthermore, the compounds of formula (I) are not very toxic; inparticular, their acute toxicity is compatible with their use asmedicaments for the treatment of diseases in which compounds having anaffinity for the beta-3 receptor find application. The compounds offormula (I) and their pharmaceutically acceptable salts can therefore beindicated, for example, in the treatment of gastrointestinal diseases,such as irritable bowel syndrome (IBD), as modulators of intestinalmotricity, or as lipolytics, antiobesity agents, antidiabetics,psychotropics, antiglaucoma agents, cicatrizants, antidepressants ortocolytics.

The use of the compounds of formula (I) above, and that of theirpharmaceutically acceptable salts and solvates, for the preparation ofabove medicaments constitutes a subsequent aspect of the presentinvention.

For such a use, an effective amount of a compound of formula (I) or ofone of its pharmaceutically acceptable salts and solvates isadministered to the mammals who require such a treatment.

The compounds of formula (I) above and their pharmaceutically acceptablesalts and solvates can be used at daily doses of 0.01 to 20 mg per kiloof body weight of the mammal to be treated, preferably at daily doses of0.1 to 10 mg/kg. In man, the dose can preferably vary from 0.5 mg to 1500 mg per day, in particular from 2.5 to 500 mg, according to the ageof the subject to be treated, the type of treatment, prophylactic orcurative, and the seriousness of the condition. The compounds of formula(I) are generally administered as a dosage unit of 0.1 to 500 mg,preferably of 0.5 to 100 mg, of active principle, one to five timesdaily.

Said dosage units are preferably formulated in pharmaceuticalcompositions in which the active principle is mixed with apharmaceutical excipient.

Thus, according to another of its aspects, the present invention relatesto pharmaceutical compositions including, as active principle, acompound of formula (I) above or one of its pharmaceutically acceptablesalts and solvates.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical,transdermal or rectal administration, the active ingredients of formula(I) above and their pharmaceutically acceptable salts and solvates canbe administered in unit administration forms, as a mixture withconventional pharmaceutical vehicles, to animals and human beings forthe treatment of the above said conditions. The appropriate unitadministration forms comprise oral forms, such as tablets, gelatincapsules, powders, granules and solutions or suspensions to be takenorally, sublingual and buccal administration forms, subcutaneous,intramuscular or intravenous administration forms, local administrationforms and rectal administration forms.

When a solid composition is prepared in the form of tablets, the mainactive ingredient is mixed with a pharmaceutical vehicle, such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets can be coated with sucrose or other appropriatematerials or can be treated so that they have a prolonged or delayedactivity and so that they continuously release a predetermined amount ofactive principle.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with a diluent and by pouring the mixture obtainedinto soft or hard gelatin capsules.

A preparation in the syrup or elixir form can comprise the activeingredient in conjunction with a sweetener, preferably a calorie-freesweetener, methylparaben and propylparaben as antiseptics, and anappropriate colorant and flavoring.

The water-dispersible powders or granules can comprise the activeingredient as a mixture with dispersing agents, wetting agents orsuspending agents, such as polyvinylpyrrolidone, and with sweeteners orflavor enhancers.

For local administration, the active principle is mixed in an excipientfor the preparation of creams or ointments or is dissolved in a vehiclefor intraocular administration, for example in the form of an eyewash.

For rectal administration, recourse is had to suppositories which areprepared with binders which melt at the rectal temperature, for examplecocoa butter or polyethylene glycols.

For parenteral administration, use is made of aqueous suspensions,saline solutions or sterile injectable solutions which comprisepharmacologically compatible dispersing and/or wetting agents, forexample propylene glycol or butylene glycol.

The active principle can also be formulated in the form ofmicrocapsules, optionally with one or more vehicles or additives.

According to another of its aspects, the present invention relates to amethod for the treatment of the pathologies which are improved by abeta-3-agonist action which comprises administering a compound offormula (I) or one of its pharmaceutically acceptable salts or solvates.

The compounds of formula (I), in particular the compounds (I) labeledwith an isotope, can also be used as laboratory tools in biochemicalassays.

The compounds of formula (I) bind to the beta-3-adrenergic receptor.These compounds can therefore be used in a standard binding assay, inwhich use is made of an organic tissue in which this receptor isparticularly abundant, and the amount of compound (I) displaced by atest compound is measured, in order to evaluate the affinity of saidcompound with respect to binding sites of this specific receptor.

Another specific subject matter of the present invention is thus areagent which can be used in biochemical assays, which comprises atleast one suitably labeled compound of formula (I).

The examples which follow give a better illustration of the invention.

Preparation 1

4-(tert-Butoxycarbonylamino)piperidine.

25 g (0.13 mol) of 4-amino-1-benzylpiperidine, 36.2 ml (0.26 mol) oftriethylamine and 31.2 g (0.143 mol) of di-tert-butyl dicarbonate aremixed in 200 ml of dimethylformamide at ambient temperature for 2 hours.The mixture is poured into water, extraction is carried out with ethylacetate and washing is carried out with water, and the product thusobtained is crystallized from 200 ml of isopropyl ether. 33 g of1-benzyl-4-(tert-butoxycarbonylamino)piperidine are obtained and arehydrogenated in a mixture of 200 ml of ethanol and 100 ml oftetrahydrofuran in the presence of 3 g of 10% Pd/C. After filtering offthe catalyst, the title compound is isolated.

M.p. 157-160° C.

Preparation 2

4-tert-Butoxycarbonylamino-1-(4-ethoxycarbonylphenylmethyl)piperidine

A mixture of 2.01 g (0.010 mol) of the product obtained in preparation 1and 2 g (0.010 mol) of 4-chloromethyl-ethoxycarbonylbenzene in 40 ml ofdimethylformamide is heated with stirring for 6 hours at 50° C. Themixture is poured into water, extraction is carried out with ethylacetate and washing is carried out with water. The product is filteredoff and dried. The crude product thus obtained is purified by flashchromatography, elution being carried out with a cyclohexane/ethylacetate=1:1 mixture. The title compound is obtained.

M.p. 74-76° C.

Preparation 3

4-Amino-1-(4-ethoxycarbonylphenylmethyl)piperidine

The product obtained by preparation 2 is heated at reflux for 5 hours ina solution comprising 15 ml of ethyl acetate and 15 ml of hydrochloricacid in ethyl acetate (about 3N). After cooling, filtration is carriedout, washing with acetone is carried out and the product is dried underreduced pressure. The title product is obtained in hydrochloridedihydrate form by crystallization from an ethanol solution.

M.p. 290-293° C.

Preparation 4

4-tert-Butoxycarbonylamino-1-(4-ethoxycarbonylphenyl)piperidine

21.6 g (0.10 mol) of the product from preparation 1 are heated at 80° C.for 55 hours with 9.06 g (0.01 mol) of(4-ethoxycarbonyl-1-fluoro)benzene and 14.9 g of K₂CO₃ in 200 ml ofdimethylformamide. The K₂CO₃ is filtered off, the solution is pouredinto water and extracted with ethyl acetate, and the solvent isevaporated. The crude reaction product is purified by flashchromatography, elution being carried out with a cyclohexane/ethylacetate=8:2 mixture. The title product is obtained and is crystallizedfrom ethyl acetate.

M.p. 138-140° C.

Preparation 5

4-Amino-1-(4-ethoxycarbonylphenyl)piperidine hydrochloride

7.94 g (0.023 mol) of the product from preparation 4 are dissolved in 60ml of ethyl acetate, and 80 ml of a 3N solution of hydrochloric acid inethyl acetate are added. The mixture is heated at reflux for 5 hours,the solvent is evaporated, acetone is added and filtration is carriedout. The title product is obtained and is crystallized from ethanol.

M.p. 240-242° C. (hydrochloride)

Preparation 6

4-tert-Butoxycarbonylamino-1-(4-methoxycarbonylphenyl)piperidine

3 mg (0.01 mmol) of Pd(OAc)₂, 10 mg (0.015 mmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 215 mg (1.2 mmol)of 4-bromo-1-methoxycarbonylbenzene and 240 mg of the product frompreparation 1 (1.2 mmol) are added to a suspension of 456 mg of Cs₂CO₃in 2 ml of anhydrous toluene. The mixture is heated at 110° C. and,after 2 days, 2 ml of dioxane, 3 mg of Pd(OAc)₂ and 10 mg of BINAP areadded. The mixture is heated for a further two days at 110° and then thereaction is halted. The mixture is poured into water and extracted withethyl acetate. The product is purified by flash chromatography, elutionbeing carried out with an ethyl acetate/cyclohexane mixture.

M.p. 162-165° C.

Preparation 7

4-(Phenylmethoxy)-3-(N-tert-butoxycarbonyl-N-methansulfonylamino)-1-(2,3-epoxypropoxy)benzeneand its (2S) isomer

The title product was obtained according to the procedure disclosed inWO 96/04233 (procedure 96).

Preparation 8

4-Benzyloxy-3-methylsulfinyl-1-[(2,3-epoxypropoxy)]-benzene

The title product was obtained following the procedure disclosed in U.S.Pat. No. 4,396,629.

Preparation 9

4-Benzyloxy-1-[(2,3-epoxypropoxy)]benzene

The title product was obtained following the procedure disclosed in WO96/04233 (procedure 7).

Preparation 10

4-tert-Butoxycarbonylamino-1-(4-hydroxycarbonylphenyl)piperidine

2.19 g (0.0063 mol) of the product from preparation 4 are dissolved in30 ml of ethanol and 30 ml of THF, and 20 ml of water and 12.6 ml(0.0126 mol) of a 1N NaOH solution are added thereto. The mixture isstirred at ambient temperature for 24 hours and then at 40° C. for 8hours. Acetic acid is added until a pH of 5 is achieved and the solventis evaporated under reduced pressure. The residue is taken up in waterand the solid is filtered off and recrystallized from 200 ml of ethanol.The title product is obtained in the form of a white solid.

M.p. >300° C.

Preparation 11

4-Amino-1-[4-(N-normal-butylaminocarbonyl)phenyl]-piperidinehydrochloride hydrate

11a.4-tert-Butoxycarbonylamino-1-[4-(N-normal-butylaminocarbonyl)phenyl]piperidine

2.5 g (0.0078 mol) of the product from preparation 10 are dissolved in80 ml of methylene chloride, and 3.45 g (0.0078 mol) of BOP, 8 ml(0.0078 mol) of normal-butylamine and 1.7 ml (0.012 mol) oftriethylamine are added thereto. The mixture is stirred at 40° C. for 8hours, the solvent is evaporated under reduced pressure, and the residueis taken up in ethyl acetate and washed with a saturated sodiumbicarbonate solution. The solid formed is filtered off and crystallizedfrom isopropanol. The title compound is obtained in the form of a whitesolid.

M.p. 208-210° C.

11b. 4-Amino-1-[4-(N-normal-butylaminocarbonyl)phenyl]-piperidinehydrochloride hydrate

By carrying out the operation as described in preparation 5 but usingthe product from the preceding stage instead of the product frompreparation 4, the title compound is obtained.

M.p. 231-235° C. (hydrochloride hydrate)

Preparation 12

4-Amino-1-[4-(N,N-diethylaminocarbonyl)phenyl]-piperidinedihydrochloride

12a.4-tert-Butoxycarbonylamino-1-[4-(N,N-diethylaminocarbonyl)phenyl]piperidine

By carrying out the operation as described in preparation 11a but usingdiethylamine instead of normal-butylamine, the title compound isobtained.

M.p. 113-115° C.

12b. 4-Amino-1-[4-(N,N-diethylaminocarbonyl)phenyl]-piperidinedihydrochloride

By carrying out the operation as described in preparation 11b but usingthe product from the preceding stage instead of the product frompreparation 11a, the title compound is obtained.

M.p. 232-234° C. (dihydrochloride)

Preparation 13

4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-(butansulfonyl)amino)-1-[((2S)-2,3-epoxypropoxy)]benzene

13a. 4-Benzyloxy-3-(butansulfonylamino)benzene acetate

5.0 g (0.00194 mol) of 3-amino-4-benzyloxybenzene acetate are mixedunder a nitrogen atmosphere in 15 ml of methylene chloride, and 3.3 mlof triethylamine (0.0236 mol) and 3.3 ml (0.0245 mol) of 1-butansulfonylchloride are added thereto. The mixture is stirred at ambienttemperature overnight and afterwards at 30° C. for 4 hours. Washing withwater is carried out, the two phases are separated, the organic phase isdried over sodium sulfate and filtered, and the solvent is evaporatedunder reduced pressure. Purification is carried out by chromatography ona column of silica gel, elution being carried out with acyclohexane/ethyl acetate=9:1 mixture. The title compound is obtained.

M.p. 104-106° C.

13b. 4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-(butansulfonyl)amino)benzeneacetate

3.4 g (0.009 mol) of the product from the preceding stage are mixed in70 ml of methylene chloride, and 2.4 g (0.0108 mol) of di-tert-butyldicarbonate and 0.22 g (0.0018 mol) of 4-dimethylaminopyridine are addedthereto. The mixture is stirred at ambient temperature for 3 hours, thesolvent is evaporated and the residue is purified by chromatography on acolumn of silica gel, elution being carried out with a cyclohexane/ethylacetate=8:2 mixture. The title compound is obtained.

M.p. 74-76° C.

13c. 4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-(butansulfonyl)amino)phenol

4 g (0.0083 mol) of the product from the preceding stage are mixed in 80ml of methanol, and 9.9 g (0.0099 mol) of 1N NaOH are added thereto. Themixture is stirred at ambient temperature for 30 minutes, citric acid isadded until a pH of 6 is achieved and the solvent is evaporated. Theresidue is taken up with ethyl acetate, washing with water is carriedout, the two phases are separated, the organic phase is dried oversodium sulfate and filtered, and the solvent is evaporated under reducedpressure. The title compound is obtained.

M.p. 131-133° C.

13d.4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-(butansulfonyl)amino)-1-[((2S)-2,3-epoxypropoxy)]-benzene

3.0 g (0.0062 mol) of the product from the preceding stage are mixed in60 ml of acetone, and 2.8 g of ground anhydrous potassium carbonate and2.0 g (0.0077 mol) of (2S)-(+)-glycidyl nosylate are added thereto. Themixture is heated at reflux for 20 hours and filtered, the solvent isevaporated and the residue is purified by chromatography on a column ofsilica gel, elution being carried out with a cyclohexane/ethylacetate=75/25 mixture. The title compound is obtained.

M.p. 87-89° C. [α]_(D)=+4.9° C. (c, 1% in methanol)

Preparation 14

4-Benzylcarbonyloxy-3-(N-tert-butoxycarbonyl-N-propansulfonylamino)-1-[((2S)-2,3-epoxypropoxy)]benzene

By carrying out the operation as described in preparation 13 but using1-propansulfonyl chloride instead of 1-butansulfonyl chloride, the titlecompound is obtained.

[α]_(D)=+4.5° C. (c, 1% in ethanol)

Preparation 15

4-Benzyloxy-3-(N-methylaminosulfonyl)-1-[((2S)-2,3-epoxypropoxy)]benzene]

15a. 2,5-Dihydroxy-N-methylbenzenesulfonamide

2.27 g (7.75 mmol) of 4-acetyloxy-2-(chlorosulfonyl)phenyl acetate, asobtained according to the process described in J. Am. Chem. Soc., 1951,73, 2558-2565, are stirred at ambient temperature for 2 hours in 8 ml oftetrahydrofuran and 8 ml of a solution of methylamine (77.5 mmol) inmethanol. The solvent is evaporated and the residue is taken up in 10 mlof acidified water. Extraction is carried out with ethyl acetate, thetwo phases are separated, the organic phase is dried over sodium sulfateand filtered, and the solvent is evaporated under reduced pressure.Purification is carried out by chromatography on a column of silica gel,elution being carried out with a hexane/ethyl acetate=1/2 mixture. Thetitle compound is obtained.

15b.2-Hydroxy-5-[[tert-butyl(dimethyl)silyl]oxy]-N-methylbenzenesulfonamide

1.07 g (7.10 mmol) of tert-butyldimethylsilyl chloride (TBDMSCl) and1.76 ml of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) are mixed and thismixture is added to a solution of 1.4 g (6.9 mmol) of the product fromthe preceding stage in 20 ml of methylene chloride and 5 ml oftetrahydrofuran. The mixture is stirred at ambient temperature for 2hours. Washing is carried out with water and with 20 ml of a 5% H₃PO₄solution and, afterwards, with a sodium bicarbonate solution. The twophases are separated, the organic phase is dried over sodium sulfate andfiltered, and the solvent is evaporated under reduced pressure. Thetitle compound is obtained.

15c. 4-[[tert-Butyl(dimethyl)silyl]oxy]-2-(N-methylaminosulfonyl)phenylbenzoate

1.8 g (5.67 mmol) of the product from the preceding stage are mixedunder a nitrogen atmosphere in 10 ml of methylene chloride, and 1.8 mlof pyridine and 1.3 ml of benzoyl chloride at 0° C. are added thereto.The mixture is stirred at ambient temperature for 3 hours and then asodium bicarbonate solution is added thereto. Extraction is carried outwith ethyl acetate, the two phases are separated, the organic phase isdried over sodium sulfate and filtered, and the solvent is evaporatedunder reduced pressure. The residue is purified by chromatography on acolumn of silica gel, elution being carried out with a hexane/ethylacetate=2/1 mixture. The title compound is obtained.

15d. 4-Hydroxy-2-(N-methylaminosulfonyl)phenyl benzoate

1.7 g (4.03 mmol) of the product from the preceding stage are mixedunder a nitrogen atmosphere in 80 ml of a 1% solution of hydrochloricacid in 95% ethanol. The mixture is stirred at ambient temperature for 3hours. 100 ml of water are added thereto, extraction is carried out withethyl acetate, the two phases are separated, the organic phase is driedover sodium sulfate and filtered, and the solvent is evaporated underreduced pressure. The title compound is obtained.

M.p. 168-170° C.

15e.4-Benzyloxy-3-(N-methylaminosulfonyl)-1-[((2S)-2,3-epoxypropoxy)]benzene

By carrying out the operation as described in preparation 13d but usingthe product from the preceding stage instead of the product from stage13c, the title compound is obtained.

[α]_(D)=+19.9° (c=1% in chloroform)

Preparation 16

4-tert-Butoxycarbonylamino-1-(4-cyanophenyl)piperidine

By carrying out the operation as described in preparation 6 but using4-bromocyanobenzene instead of 4-bromo-1-methoxycarbonylbenzene, thetitle compound is obtained.

M.p. 188-189° C.

Preparation 17

4-Amino-1-(4-cyanophenyl)piperidine

By carrying out the operation as described in preparation 5 but usingthe product from preparation 16 instead of the product from preparation4. The base is released with ammonia and extraction with ethyl acetate,the title compound is obtained.

M.p. 78-80° C.

Preparation 18

4-tert-Butoxycarbonylaminomethyl-1-(4-ethoxycarbonylphenyl)piperidine

By carrying out the operation as described in preparation 4 but using4-(tert-butoxycarbonylaminomethyl)piperidine (disclosed in WO 99/65895)instead of the 4-(tert-butoxycarbonylamino)piperidine of preparation 1,the title compound is obtained.

Preparation 19

4-Aminomethyl-1-(4-ethoxycarbonylphenyl)piperidine hydrochloride

By carrying out the operation as described in preparation 5 but usingthe product from preparation 18 instead of the product from preparation4, the title compound is obtained.

Preparation 20

4-Benzyloxy-3-(N-benzyloxycarbonyl-N-methansulfonylamino)-1-[((2S)-2,3-epoxypropoxy)]benzene

20a. 4-Benzyloxy-3-(N-benzyloxycarbonyl-N-methansulfonylamino)benzeneacetate

1 g (0.003 mol) of 4-benzyloxy-3-(methansulfonylamino)benzene acetate(WO 96/04233) in 20 ml of methylene chloride, 0.50 ml (0.0033 mol) of95% benzyl chloroformate, 0.006 g of dimethylaminopyridine and 0.46 ml(0.0033 mol) of triethylamine is stirred at 50° C. for 10 hours. Thesolvent is evaporated, the residue is taken up in methylene chloride,washing with water is carried out, the two phases are separated, theorganic phase is dried over sodium sulfate and filtered, and the solventis evaporated under reduced pressure. Purification is carried out bychromatography on a column of silica gel, elution being carried out withethyl acetate. The title compound is obtained.

M.p. 140-142° C.

20b. 4-Benzyloxy-3-(N-benzyloxycarbonyl-N-methansulfonylamino)phenol

By carrying out the operation as described in preparation 13c but usingthe product from the preceding stage instead of the product frompreparation 13b, the title compound is obtained.

M.p. 138-140° C.

20c.4-Benzyloxy-3-(N-benzyloxycarbonyl-N-methansulfonylamino)-1-[((2S)-2,3-epoxypropoxy)]benzene

By carrying out the operation as described in preparation 13d but usingthe product from the preceding stage instead of the product from stage13c, the title compound is obtained.

M.p. 78-80° C.; [α]_(D)=+4.4° (c=0.5% in methanol)

Preparation 21

4-Amino-1-(4-tert-butoxycarbonylphenyl)piperidine

1.5 g (7.5 mmol) of 4-(2,5-dimethylpyrrol-1-yl)piperidine, 60 ml ofdimethylformamide and 1.6 g (7.5 mmol) of the tert-butyl ester of4-fluorobenzoic acid and 2.6 ml of diisopropylethylamine are mixed undernitrogen. The mixture is heated with stirring for 6 hours at 90° C. andafterwards is stirred at ambient temperature for 15 hours. 1.04 g (7.5mmol) of potassium carbonate are added thereto and the mixture is heatedat 90° C. for 5 days. The mixture is poured into water, extraction iscarried out with ethyl acetate and washing is carried out with water.The two phases are separated, the organic phase is dried over sodiumsulfate and filtered, and the solvent is evaporated under reducedpressure. Purification is carried out by chromatography on a column ofsilica gel, elution being carried out with a hexane/ethyl acetate=3/1mixture.4-(2,5-Dimethylpyrrol-1-yl)-1-(tert-butoxycarbonylphenyl)piperidine isisolated. 250 mg of NH₂OH.HCl and 0.7 ml of ethanol are mixed undernitrogen and stirred for 30 minutes. 67 mg (1.2 mmol) of KOH in 0.3 mlof a 1/1 ethanol/water solution and 300 mg (0.084 mmol) of the aboveintermediate product in 0.5 ml of ethanol are added thereto. The mixtureis heated at 80° C. for 12 hours. Extraction is carried out with ethylacetate, KOH is added to the aqueous phase until a pH of 9 is achieved,and extraction is carried out with ethyl acetate. The two phases areseparated, the organic phase is dried over sodium sulfate and filtered,and the solvent is evaporated under reduced pressure. The title compoundis obtained.

M.p. 89-91° C.

Preparation 22

4-tert-Butoxycarbonylamino-1-(4-aminocarbonylphenyl)piperidine

By carrying out the operation as described in preparation 4 but using4-fluorobenzamide instead of 4-ethoxycarbonyl-1-fluorobenzene, the titlecompound is obtained.

M.p. >270° C.

Preparation 23

4-Amino-1-(4-aminocarbonylphenyl)piperidine hydrochloride

By carrying out the operation as described in preparation 5 but usingthe product from preparation 22 instead of the product from preparation4, the title compound is obtained.

EXAMPLE 1

3-[1-(4-Ethoxycarbonylphenylmethyl)piperidin-4-yl-amino]-1-(4-hydroxyphenoxy)-2-propanol

1a.3-[1-(4-Ethoxycarbonylphenylmethyl)piperidin-4-ylamino]-1-(4-methoxyethoxymethoxyphenoxy)-2-propanol

0.86 g (0.0033 mol) of4-(methoxyethoxymethoxy)-1-(2,3-epoxypropoxy)benzene and 0.83 g (0.0033mol) of the product obtained in preparation 3 in the free base form areheated at reflux for 17 hours in 40 ml of ethanol. The solvent isevaporated under reduced pressure and the product is dried. The crudereaction product is purified by flash chromatography, elution beingcarried out with methanol. The product is crystallized from isopropylether.

M.p. 73-75° C.

1b.3-[1-(4-Ethoxycarbonylphenylmethyl)piperidin-4-yl-amino]-1-(4-hydroxyphenoxy)-2-propanoldioxalate

A mixture comprising 0.7 g (0.0014 mol) of the product obtained in thepreceding stage and 1.1 ml (0.014 mol) of CF₃COOH in 40 ml of methylenechloride is heated at 40° C. for 8 hours. The solvent is evaporated andammonia is added. Extraction is carried out with ethyl acetate, theextract is dried and the solvent is evaporated. The crude reactionproduct is purified by flash chromatography, elution being carried outwith methylene chloride/methanol=9:1. The title compound is obtained inthe base form. Its dioxalate is prepared using oxalic acid in acetone.

M.p. 180-184° C. (dioxalate)

EXAMPLE 2

3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]1-1(4-hydroxyphenoxy)-2-propanol

2a.3-[1-(4-Ethoxycarbonylphenyl)piperidinylamino]-1-(4-benzyloxyphenoxy)-2-propanol

1.03 g (0.004 mol) of the product from preparation 9 and 1 g (0.004 mol)of the product from preparation 5 in the base form are heated at refluxfor 20 hours in 50 ml of ethanol. The solvent is evaporated and thecrude reaction product is purified by flash chromatography, elutionbeing carried out with the CH₂Cl₂/methanol=9:1 mixture. The titleproduct is obtained.

M.p. 112-114° C.

2b.3-[1-(4-Ethoxycarbonylphenylmethyl)piperidin-4-ylamino]-1-(4-hydroxyphenoxy)-2-propanol

1.15 g (0.0023 mol) of the product from the preceding stage arehydrogenated at 40° C. in 20 ml of ethanol+20 ml of THF in the presenceof 0.1 g of 10% palladium-on-carbon at ambient pressure for eight hours.150 ml of hydrogen are absorbed.

The mixture is filtered and the solvent is evaporated. The residue iscrystallized from ethyl acetate. The title product is obtained.

M.p. 158-161° C.

EXAMPLE 3

3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-2-propanoland its (2S) isomer

3a.3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-benzyloxy)-3-(methansulfonylamino)phenoxy]-2-propanol

1 g (0.004 mol) of the product from preparation 5 in the base form ismixed with 1.35 g (0.003 mol) of the product from preparation 7 and 0.2g of lithium perchlorate in 50 ml of CH₃CN. The mixture is left stirringfor 24 hours at ambient temperature and is then heated at 40° for eighthours.

The solvent is evaporated and the product thus obtained is treated at40° C. for eight hours with a solution of hydrochloric acid in ethylacetate. The solvent is evaporated, the residue is treated with anNaHCO₃ solution and extraction is carried out with ethyl acetate. Thesolvent is again evaporated and the crude reaction product is purifiedby flash chromatography, elution being carried out with aCH₂Cl₂/methanol=9:1 mixture. The title product is obtained.

M.p. 130-132° C.

3b.3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-2-propanol

0.8 g (0.0013 mol) of the product from the preceding stage are subjectedto hydrogenation in the presence of 0.1 g of palladium-on-carbon (10%)in 15 ml of ethanol+15 ml of THF. After reacting for eight hours at 40°and at ambient pressure, the mixture is filtered and the solvent isevaporated. The crude reaction product is purified by flashchromatography, elution being carried out with a CH₂Cl₂/methanol=9:1mixture. The title product is obtained and is crystallized fromisopropanol.

M.p. 140-143° C.

Isomer (2S)

By carrying out the operation according to the above stages 3a and 3bbut using the product from preparation 7 in the optically active (2S)form, the (2S) enantiomer of the title compound is obtained.

M.p. 96-99° C. (hydrated form).

EXAMPLE 4

3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methysulfinyl)phenoxy]-2-propanoland its (2S) isomer

4a.3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-benzyloxy)-3-(methysulfinyl)phenoxy]-2-propanol

0.8 g (0.0032 mol) of the product from preparation 5 in the base form isheated at reflux overnight with 1 g (0.0031 mol) of the product frompreparation 8 in 50 ml of ethanol. The solvent is evaporated and thecrude reaction product is purified by flash chromatography, elutionbeing carried out with a CH₂Cl₂/methanol=95:5 mixture. The title productis obtained.

M.p. 135-137° C.

4b.3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methysulfinyl)phenoxy]-2-propanoltrifluoroacetate

0.98 g (0.0017 mol) of the product from the preceding stage is heated at55° C. for seven hours in 20 ml of CF₃COOH. The solvent is evaporated, abicarbonate solution is added and extraction is carried out with ethylacetate. The solvent is evaporated and the crude reaction product ispurified by flash chromatography, elution being carried out with aCH₂Cl₂/methanol=9:1 mixture. The title product is obtained.

M.p. 78-80° C. (trifluoroacetate).

EXAMPLE 5

3-[1-(4-N-Butylaminocarbonylphenyl)piperidinylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-(2S)-2-propanol

5a.3-[1-(4-N-Butylaminocarbonylphenyl)piperidinylamino]-1-[(4-benzyloxy)-3-(methansulfonylamino)phenoxy]-(2S)-2-propanol

0.72 g (0.0026 mol) of the product from preparation 11b in the base formis heated at reflux overnight with 1.08 g (0.0024 mol) of the productfrom preparation 7 in 25 ml of ethanol. The solvent is evaporated andthe crude reaction product is purified by flash chromatography, elutionbeing carried out with methanol. The product thus obtained is treated at70° for 4 hours with a solution of hydrochloric acid in ethyl acetate.The solvent is evaporated, the residue is treated with an NaHCO₃solution and extraction is carried out with ethyl acetate. The solventis again evaporated. The title product is obtained.

M.p. 123-133° C.

5b.3-[1-(4-N-Butylaminocarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-(2S)-2-propanol

By carrying out the operation as described in example 3b but using theproduct from the preceding stage instead of the product from stage 3a,the title compound is obtained.

M.p. 146-148° C.

EXAMPLE 6

3-[1-(4-N,N-Diethylminocarbonylphenyl)piperidiny-4-ylamino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]]-(2S)-2-propanol

By carrying out the operation as described in example 5 but using theproduct from preparation 12b in the base form instead of the productfrom preparation 11b, the title compound is obtained.

M.p. 67-70° C.

EXAMPLE 7

3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(N-butansulfonylamino)phenoxy]-(2S)-2-propanoland its hydrochloride

By carrying out the operation as described in example 5 but using theproduct from preparation 13d instead of the product from preparation 7and the product from preparation 5 in the base form instead of theproduct from preparation 11b, the title compound is obtained. Thehydrochloride is prepared using ethyl acetate and hydrochloric acid.

M.p. 192-195° C. (hydrochloride).

EXAMPLE 8

3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(N-propansulfonylamino)phenoxy]-(2S)-2-propanol

By carrying out the operation as described in example 5 but using theproduct from preparation 14 instead of the product from preparation 7and the product from preparation 5 in the base form instead of theproduct from preparation 11b, the title compound is obtained.

M.p. 63-65° C.

EXAMPLE 9

3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(methylaminosulfonyl)phenoxy]-(2S)-2-propanol

0.56 g (0.0015 mol) of the product from preparation 15e is heated atreflux overnight with 0.38 g (0.0015 mol) of the product frompreparation 5 in the base form in 10 ml of DMF. The solvent isevaporated and the crude reaction product is purified by flashchromatography, elution being carried out with methanol. The titleproduct is obtained.

M.p. 87° C.

EXAMPLE 10

3-[1-(4-Cyanophenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(N-methansulfonylamino)phenoxy]-(2S)-2-propanol

By carrying out the operation as described in example 5 but using theproduct from preparation 17 instead of the product from preparation 11b,the title compound is obtained.

M.p. 78-80° C.

EXAMPLE 11

3-[1-(4-tert-Butoxycarbonylphenyl)piperidin-4-ylamino]-1-[(4-hydroxy)-3-(N-methansulfonylamino)phenoxy]-(2S)-2-propanol

By carrying out the operation as described in example 3 but using theproduct from preparation 21 instead of the product from preparation 5and the product from preparation 20 instead of the product frompreparation 7, the title compound is obtained.

EXAMPLE 12

3-[[1-(4-Ethoxycarbonylphenyl)-4-piperidinylmethyl]amino]-1-[(4-hydroxy)-3-(methansulfonylamino)phenoxy]-(2S)-2-propanol

By carrying out the operation as described as for example 5 but usingthe product from preparation 19 instead of the product from preparation11b, the title compound is obtained.

EXAMPLE 13

5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxyphenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

13a. 5-Amino-2-(4-tert-butoxycarbonylaminopiperidino)pyridine

2 g (0.0062 mol) of 5-nitro-2-(4-tert-butoxycarbonylpiperidino)pyridineare mixed in 40 ml of ethanol and 60 ml of tetrahydrofuran. 0.4 g of 10%Pd/C are added and hydrogenation is carried out at 40° C. at ambientpressure for 7 hours. The mixture is filtered, the solvent is evaporatedand 2 g of the title compound are obtained in the solid form.

13b.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-tert-butoxycarbonylaminopiperidino)pyridine

0.4 g (0.0013 mol) of the product from the preceding stage is dissolvedin 10 ml of pyridine. 0.3 g (0.0013 mol) of 4-isopropylbenzenesulfonylchloride is added thereto and the mixture is heated at 50° C. for 2hours. The solvent is evaporated (with the precautions for hydrochloricacid) and the residue is taken up in ethyl acetate and water. The twophases are separated, the organic phase is washed with water and dried,and the solvent is evaporated under reduced pressure. Purification iscarried out by flash chromatography on a column of silica gel, elutionbeing carried out with a cyclohexane/ethyl acetate=6/4 mixture. Thetitle product is obtained.

M.p. 208-209° C.

13c.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-aminopiperidino)pyridinedihydrochloride

2.1 g (0.0042 mol) of the product from the preceding stage are heated toreflux for 4 hours in 20 ml of ethyl acetate and 20 ml of anapproximately 3N solution of gaseous hydrochloric acid in ethyl acetate.The solvent is evaporated under reduced pressure, the residue is takenup in acetone and filtered, the precipitate is washed with acetone and1.8 g of the title product are obtained, which product is crystallizedfrom ethanol.

M.p. 270-273° C.

13d.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-(benzyloxy)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

0.239 g (0.932 mol) of 4-benzyloxy-1-(2,3-epoxypropoxy)benzene and 0.35g (0.935 mmol) of the product from the preceding stage in the base formare heated at reflux for 20 hours in 10 ml of ethanol. The solvent isevaporated under reduced pressure and purification is carried out byflash chromatography on a column of silica gel, elution being carriedout with a methylene chloride/methanol=95/5 mixture. 0.37 g of the titleproduct is obtained in the form of a glassy product.

13e.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxyphenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

0.37 g (0.586 mmol) of the product from the preceding stage, 10 ml ofethanol, 10 ml of tetrahydrofuran and 0.037 g of 10% Pd/C are mixed.Hydrogenation is carried out at 40° C. and ambient pressure for 8 hours.The mixture is filtered, the solvent is evaporated under reducedpressure and the residue is purified by flash chromatography on a columnof silica gel, elution being carried out with a 9/1 methylenechloride/methanol mixture. The title product is obtained.

M.p. 75-78° C.

EXAMPLE 14

14a.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-benzyloxy)-3-(methylsulfinyl)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

0.27 g (0.00084 mol) of4-benzyloxy-3-methylsulfinyl-1-[(2,3-epoxypropoxy)]benzene (preparedaccording to U.S. Pat. No. 4,396,629/example 3) and 0.33 g (0.00088 mol)of the product from example 13c) in the base form are heated at refluxovernight in 10 ml of ethanol. The solvent is evaporated and the crudereaction product is purified by flash chromatography, elution beingcarried out with a CH₂Cl₂/methanol=9/1 mixture. The title product isobtained in the form of a glassy solid.

14b.5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxy-3-(methylsulfinyl)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

0.4 g (0.0006 mol) of the product from the preceding stage is heated at55° C. for 5 hours in 10 ml of CF₃COOH. The solvent is evaporated underreduced pressure, the crude product is dissolved in ethyl acetate,washing is carried out using a saturated aqueous bicarbonate solutionand drying is carried out. The product thus obtained is purified byflash chromatography, elution being carried out with aCH₂Cl₂/methanol=9/1 mixture and then with a CH₂Cl₂/methanol=85/15mixture. The title product is obtained.

M.p.: 128-130° C.

EXAMPLE 15

5-[((4-Isopropylphenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxy-3-methansulfonylamino)phenoxy)-(2S)-2-hydroxypropyl)amino)piperidino)pyridine

By carrying out the operation as described in example 5 but using theproduct from example 13c in the base form instead of the product frompreparation 11b, the title compound is obtained.

EXAMPLE 16

5-[((4-Bromophenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxy-3-(methylsulfinyl)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

16a.5-[((4-Bromophenyl)sulfonyl)amino]-2-[4-(tert-butoxycarbonylamino)piperidino]pyridine

By carrying out the operation as in example 13b but using4-bromobenzenesulfonyl chloride instead of 4-isopropylbenzenesulfonylchloride, the title compound is obtained.

16b.5-[((4-Bromophenyl)sulfonyl)amino]-2-(4-((3-(4-hydroxy-3-(methylsulfinyl)phenoxy)-2-hydroxypropyl)amino)piperidino)pyridine

By carrying out the operation as in example 13c, the product from thepreceding stage is deprotected. 1.2 g of this product, 1.12 ml oftriethylamine and 0.738 g of4-benzyloxy-3-methylsulfinyl-1-[(2,3-epoxypropoxy)]benzene (preparedaccording to U.S. Pat. No. 4,396,629/example 3) are heated at reflux for12 hours in 100 ml of ethanol. The solvent is evaporated andpurification is carried out by flash chromatography, elution beingcarried out with a CH₂Cl₂/methanol/NH₃=90/10/1 mixture. A mixturecontaining 680 mg of the product thus obtained and 30 ml of CF₃COOH isheated at 55° C. for 5 hours. The solvent is evaporated and the residueis treated with a saturated sodium bicarbonate solution. Extraction iscarried out with ethyl acetate, the extract is dried and the solvent isevaporated. The crude reaction product is purified by flashchromatography, elution being carried out with methylenechloride/methanol/NH₃=90/10/1. The title compound is obtained in thebase form.

M.p. 147° C.

EXAMPLE 17

3-[1-(4-Ethoxycarbonylphenyl)piperidin-4-ylamino]-1-(4-hydroxy-3-(methylsulfonyl)phenoxy)-(2S)-2-propanol

By carrying out the operation as described in example 14 but using4-benzyloxy-3-methylsulfonyl-1-((2S)-2,3-epoxypropoxy)benzene (disclosedin WO 99/65895, ex. 67) instead of4-benzyloxy-3-methylsulfinyl-1-[(2,3-epoxypropoxy)]benzene and theproduct from preparation 5 in the base form instead of the product fromexample 13c), the title compound is obtained.

M.p. 83-85° C.; [α]_(D)=+1.00 (c=1% in methanol)

EXAMPLE 18

3-[1-[4-((4-Isopropylphenyl)sulfonylamino)phenyl]-piperidinylamino]-1-(4-hydroxy-3-(methansulfonylamino)phenoxy)-(2S)-2-propanol

By carrying out the operation as described in example 5 but using4-amino-1-[4-((4-isopropylphenyl)sulfonylamino)phenyl]piperidine insteadof the product from preparation 11b, the title compound is obtained.

M.p. 90-93° C.

EXAMPLE 19

3-[1-[4-((4-Bromophenyl)sulfonylamino)phenyl]-piperidinylamino]-1-(4-hydroxy-3-(methansulfonylamino)phenoxy)-(2S)-2-propanol

0.95 g (0.0023 mol) of4-amino-1-[4-((4-bromophenyl)sulfonylamino)phenyl]piperidine and 1.1 g(0.0024 mol) of the product from preparation 7, (2S) isomer, are heatedunder reflux for 12 hours in 100 ml of ethanol. The solvent isevaporated and purification is carried out by flash chromatography,elution being carried out with a CH₂Cl₂/methanol=80/20 mixture. Amixture containing 680 mg of the product thus obtained and 30 ml ofCF₃COOH is heated at 55° C. for 5 hours. The solvent is evaporated andthe residue is treated with a saturated sodium bicarbonate solution.Extraction is carried out with ethyl acetate, the extract is dried andthe solvent is evaporated. The crude reaction product is purified byflash chromatography, elution being carried out with methylenechloride/methanol 90/10. The title compound is obtained.

M.p. 105-108° C.

1. A compound of formula (I)

where R₁ represents a hydrogen or halogen atom or an—S(O)_(z)—(C₁-C₄)alkyl, —S(O)_(z)—(C₁-C₄)R₃, —SO₂—NH—(C₁-C₄)alkyl,—NHCO(C₁-C₄)alkyl, —CO(C₁-C₄)alkyl or —NHSO₂—(C₁-C₄)alkyl group; m and nindependently represent 0, 1 or 2; A represents a group of formula (a)or (b):

where x is N or CH; R₂ represents an —SO₂—R₃, —CO—R₃ or—CO—(C₁-C₄)-alkyl group; R₃ represents a phenyl group, optionallysubstituted by a (C₁-C₄)alkyl or (C₁-C₄)alkoxy group, one or two halogenatoms or a heterocycle; R₄ represents a hydrogen or halogen atom or a(C₁-C₆)alkyl, (C₁-C₄)alkoxy, —COOH, —COO(C₁-C₄)alkyl, —CN, —CONR₅R₆,—NO₂, or —SO₂NR₅R₆ group; z is 1 or 2; R₅ and R₆ independently representa hydrogen atom or a (C₁-C₄)alkyl, phenyl or phenyl(C₁-C₄)alkyl group;or a salts or solvates thereof.
 2. A compound according to claim 1,where A is a group (a), X is N and the NHR₂ group is in the 5 positionof the pyridine.
 3. A compound according to claim 1, where n and m arezero.
 4. A compound according to claim 1, where the (C₁-C₄)alkyl groupis a methyl or ethyl group.
 5. A compound according to claim 1, where Ais a group (b) and the R₄ group is in the 4 position of the benzene. 6.A compound according to claim 1, where A is a group (b) and R₄ is chosenfrom —COOH, —COOHC₁-C₄)alkyl, —CN, —NO₂, —CONR₂R₃, and —SO₂NR₅R₆.
 7. Aprocess for the preparation of the compounds of formula (I) wherein acompound of formula (II)

in which R₁ is as indicated in claim 1, P′ is a protective group and Lis a group of formula (c) or (d)

where Gp is a leaving group, is reacted with an amine of formula (III)

in which n and m are as defined in claim 1, the group P′ being cleavedand the compound of formula (I) thus obtained optionally being convertedinto one of its salts.
 8. A pharmaceutical composition comprising, asactive principle an affective amount of the compound as claimed inclaim
 1. 9. A pharmaceutical composition comprising, as activeprinciple, an effective amount of the compound as claimed in claim 2.10. A pharmaceutical composition comprising, as active principle, aneffective amount of the compound as claimed in claim
 3. 11. Apharmaceutical composition comprising, as active principle, an effectiveamount of the compound as claimed in claim
 4. 12. A pharmaceuticalcomposition comprising, as active principle, an effective amount of thecompound as claimed in claim
 5. 13. A pharmaceutical compositioncomprising, as active principle, an effective amount of the compound asclaimed in claim
 6. 14. A method for the treatment of irritable bowelsyndrome, for treating obesity, or for treating diabetes, whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 1. 15. A method forthe treatment of irritable bowel syndrome, for treating obesity, or fortreating diabetes, which comprises administering to a patient in need ofsuch treatment an effective amount of a compound according to claim 2.16. A method for the treatment of bowel syndrome, for treating obesity,or for treating diabetes, which comprises administering to a patient inneed of such treatment an effective amount of a compound according toclaim
 3. 17. A method for the treatment of irritable bowel syndrome, fortreating obesity, or for treating diabetes, which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 4. 18. A method for the treatment ofirritable bowel syndrome, for treating obesity, or for treatingdiabetes, which comprises administering to a patient in need of suchtreatment an effective amount of a compound according to claim
 5. 19. Amethod for the treatment of irritable bowel syndrome, for treatingobesity, or for treating diabetes, which comprises administering to apatient in need of such treatment an effective amount of a compoundaccording to claim
 6. 20. A method according to claim 14 for thetreatment of irritable bowel syndrome.
 21. A method according to claim15 for the treatment of irritable bowel syndrome.
 22. A method accordingto claim 16 for the treatment of irritable bowel syndrome.
 23. A methodaccording to claim 17 for the treatment of irritable bowel syndrome. 24.A method according to claim 18 for the treatment of irritable bowelsyndrome.
 25. A method according to claim 19 for the treatment ofirritable bowel syndrome.